1-[(Substituted-naphthyl)ethyl]-imidazole derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein m is the integer 1, 2 or 3; R is independently selected from the group C 1  to C 6  alkyl, C 1  to C 6  alkoxy, halo, trifluoromethyl and hydroxy when m is the integer 1, 2 or 3 and methylenedioxy when m is the integer 2; Z is hydroxymethylene, esterified hydroxymethylene, alkoxymethylene, alkylthiomethylene, carbonyl, or ketal-, thioketal- or hemithioketal- protected carbonyl, and the pharmaceutically acceptable acid addition salts thereof, are useful as anticonvulsants, anti-secretory agents and spermatocides.

The present invention relates to certain1-[(substituted-naphthyl)ethyl]imidazole derivatives. More particularly,the present invention relates to compounds of formula (I), namely:##STR2## wherein m is the integer 1, 2 or 3; R is independently selectedfrom the group C₁ to C₆ alkyl, C₁ to C₆ alkoxy, halo, trifluoromethyland hydroxy when m is the integer 1, 2 or 3 and methylenedioxy when m isthe integer 2; Z is hydroxymethylene, esterified hydroxymethylene,alkoxymethylene, alkylthiomethylene, carbonyl, or ketal-, thioketal- orhemithioketal-protected carbonyl; and the pharmaceutically acceptableacid addition salts thereof.

Compounds of formula (I) exhibit a broad spectrum of CNS relatedactivity such as anticonvulsant activity (as demonstrated by the maximalelectroshock seizure test), anorexigenic, antidepressant and musclerelaxing activity; as well as inhibition of gastric secretion,antihypertensive, spermatocidal and spermatostatic activities.

One aspect of the present invention relates to a method for treatingand/or preventing convulsions in a mammalian subject comprisingadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable acid addition saltthereof. Another aspect of the present invention relates topharmaceutical compositions useful for the treatment and/or preventionof convulsions in a mammalian subject comprising a compound of formula(I), or a pharmaceutically acceptable acid addition salt thereof, inadmixture with a pharmaceutically acceptable non-toxic carrier. For thisutility compounds of formula (I) wherein Z is carbonyl, ketal-protectedcarbonyl or alkoxymethylene are particularly preferred.

Yet another aspect of the present invention relates to a method forinhibiting gastric secretion in a mammalian subject comprisingadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable acid addition saltthereof. Still another aspect of the present invention relates topharmaceutical compositions useful for the inhibition of gastricsecretion in a mammalian subject comprising a compound of formula (I),or a pharmaceutically acceptable acid addition salt thereof, inadmixture with a pharmaceutically acceptable non-toxic carrier. For thisutility compounds of formula (I) wherein Z is thioketal-protectedcarbonyl are particularly preferred.

A further aspect of the present invention concerns a process for thepreparation of a free base compound of the formula ##STR3## wherein m isthe integer 1, 2 or 3; R is independently selected from the group C₁ toC₆ alkyl, C₁ to C₆ alkoxy, halo, trifluoromethyl and hydroxy when m isthe integer 1, 2 or 3 and methylenedioxy when m is the integer 2; Z ishydroxymethylene, esterified hydroxymethylene, alkoxymethylene,alkylthiomethylene, carbonyl, or ketal-, hemithioketal- orthioketal-protected carbonyl; or a pharmaceutically acceptable non-toxicacid addition salt thereof, which process comprises:

(a) the preparation of a compound of formula (I) wherein Z is carbonylby reaction of a halomethyl naphthyl ketone with imidazole, or

(b) the preparation of a compound of formula (I) wherein Z ishydroxymethylene by reduction of a compound of formula (I) wherein Z iscarbonyl, or

(c) the preparation of a compound of formula (I) wherein Z is esterifiedhydroxymethylene by esterification of a compound of formula (I) whereinZ is hydroxymethylene, or

(d) the preparation of a compound of formula (I) wherein Z is ketalprotected carbonyl by ketalization of a compound of formula (I) whereinZ is carbonyl, or

(e) the preparation of a compound of formula (I) wherein Z ishemithioketal-protected carbonyl by hemithioketalization of a compoundof formula (I) wherein Z is carbonyl, or

(f) the preparation of a compound of formula (I) wherein Z isthioketal-protected carbonyl by thioketalization of a compound offormula (I) wherein Z is carbonyl, or

(g) the preparation of a compound of formula (I) wherein Z isketal-protected carbonyl by reaction of a compound of the formula##STR4## wherein X is halo, with an alkali metal salt of imidazole, or

(h) the preparation of a compound of formula (I) wherein Z ishydroxymethylene by reaction of a compound of the formula ##STR5## withimidazole and/or an alkali metal salt thereof, or

(i) the preparation of a compound of formula (I) wherein Z isalkoxymethylene by alkylation of a compound of formula (I) wherein Z ishydroxymethylene, or

(j) the preparation of a compound of formula (I) wherein Z isalkylthiomethylene by conversion of a compound of formula (I) wherein Zis hydroxymethlene to a reactive ester (e.g. halide or sulfonate)followed by reaction with an alkylthiol, or

(k) optionally converting a free base to the corresponding acid additionsalt, or

(l) optionally converting an acid addition salt to the correspondingfree base.

The compounds of the present invention are represented by the formula##STR6## wherein m is the integer 1, 2 or 3; R is independently selectedfrom the group C₁ to C₆ alkyl, C₁ to C₆ alkoxy, halo, trifluoromethyland hydroxy when m is the integer 1, 2 or 3 and methylenedioxy when m isthe integer 2; Z is hydroxymethylene, esterified hydroxymethylene,alkoxymethylene, alkylthiomethylene, carbonyl, or a ketal-, thioketal-or hemithioketal-protected carbonyl; and the pharmaceutically acceptableacid addition salts thereof.

Included in the compounds of formula I are the following subgenericcompounds: ##STR7## where m is the integer 1, 2 or 3; R is independentlyselected from the group C₁ to C₆ alkyl, C₁ to C₆ alkoxy, halo,trifluoromethyl and hydroxy when m is the integer 1, 2 or 3 andmethylenedioxy when m is the integer 2; B is oxygen or sulfur; Alk is C₁to C₆ alkyl; A is hydrogen, C₁ to C₅ alkyl, or phenyl optionallysubstituted with one to three substituents independently selected fromC₁ to C₆ alkyl, C₁ to C₆ alkoxy and halo; Ke is selected from the groupketal-protected carbonyl, thioketal-protected carbonyl andhemithioketal-protected carbonyl; and the pharmaceutically acceptableacid addition salts thereof.

Of the above subgeneric compounds of formula (I), the compoundspreferred are those selected from the group (I)a, (I)b, (I)c, (I)d and(I)e selected from the group ketal-protected carbonyl andthioketal-protected carbonyl.

In the preferred compounds of formula (I)c it is particularly preferredthat the group Alk is C₁ to C₃ alkyl, most preferably methyl.

In the preferred compounds of formula (I)e it is particularly preferredthat the group Ke is ketal-protected carbonyl, most preferably derivedfrom ethylene glycol.

Of the above preferred, particularly preferred and most preferredcompounds it is further particularly preferred that R is selected fromthe group C₁ to C₄ alkyl and halo, most preferably methyl, ethyl, chloroor bromo preferably with m the integer 1 or 2 most preferably theinteger 1. In these preferred, particularly preferred and most preferredcompounds, when the side chain ##STR8## is attached to the 1-position ofthe naphthalene nucleus, it is preferred that the group R is attached atthe 4- or 7-position when m is the integer 1 or at the 2,3-; 2,6-; 3,6-;3,7-; 3,4-; 2,7-; 5,8-; or 6,7-position when m is the integer 2 and R ismethyl. When the side chain is attached to the 2-position of thenaphthalene nucleus, it is preferred that the group R is attached at the1-, 3-, 5- or 6-position when m is the integer 1, or at the 1,4-; 1,6-;3,7-; 5,8-; 6,7-; 3,6-; 4,5- or 6,8-position when m is the integer 2 andR is methyl.

In practice of the above described methods of the present invention atherapeutically effective amount of the compound of formula (I) or apharmaceutical composition containing the same is administered via anyof the usual and acceptable methods known in the art, either singly orin combination with another compound or compounds of the presentinvention or other pharmaceutical agents. These compounds orcompositions can thus be administered orally or parenterally (i.e.intramuscularly, subcutaneously and intraveneously), either in the formof solid or liquid dosages including tablets, solutions, suspensions,and the like, as discussed in more detail hereinbelow. Oraladministration is preferred.

The administration can be conducted in a single unit dosage form withcontinuous therapy or in single dosage therapy ad libitum. The method ofthe present invention may be practiced when relief of symptoms isspecifically required, i.e. therapeutically, or as continuous orprophylactic treatment.

In view of the foregoing as well as in consideration of the degree ofseverity of the condition being treated, age of subject and so forth,all of which factors are determinable by routine experimentation by oneskilled in the art, the effective dosage in accordance herewith can varyover a wide range. Generally, a therapeutically effective amount foranticonvulsant use ranges from about 0.1 to about 300 mg./kg. bodyweight per day and preferably from about 1 to about 100 mg./kg. bodyweight per day. In alternate terms, for an average adult human subject,a therapeutically effective amount in accordance herewith would be, inpreferred embodiments, from about 70 mg. to about 7 g. per day persubject. A therapeutically effective amount for inhibition of gastricsecretion ranges from about 0.1 to about 300 mg./kg. body weight per dayand preferably from about 0.25 to about 100 mg./kg. body weight per day.In alternate terms, for an average adult human subject, atherapeutically effective amount in accordance herewith would be, inpreferred embodiments from about 18 mg. to about 7 g. per day persubject.

Useful pharmaceutical carriers for the preparation of the pharmaceuticalcompositions hereof can be solids or liquids. Thus, the compositions cantake the form of tablets, pills, capsules, powders, sustained releaseformulations, solutions, suspensions, elixirs, and the like. Carrierscan be selected from the various oils, including those of petroleum,animal, vegetable or synthetic origin, for example, peanut oil, soybeanoil, mineral oil, sesame oil, and the like. Water, saline, aqueousdextrose, and glycols are preferred liquid carriers, particularly forinjectable solutions. Suitable pharmaceutical excipients include starch,cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, magnesium stearate, sodium stearate, glycerolmonostearate, sodium chloride, dried skim milk, glycerol, propyleneglycol, water, ethanol, and the like. Suitable pharmaceutical carriersand their formulations are described in "Remington's PharmaceuticalSciences" by E. W. Martin. Such compositions will, in any event, containa therapeutically effective amount of the active compound together witha suitable amount of carrier so as to prepare the proper dosage form forproper administration to the subject.

Compounds similar to those of formula (I) have been previously describedin applicant's copending applications Ser. No. 796,624, filed May 13,1977 now abandoned and Ser. No. 848,548, filed Nov. 4, 1977 now U.S.Pat. No. 4,150,153, issued Apr. 17, 1979. The disclosures in saidcopending applications are incorporated by reference herein.

The compounds of the present invention may be prepared according tomethods well known in the art. For example, compounds of formula (I)dwherein Z is carbonyl may be prepared in a manner analogous to thatdescribed in U.S. Pat. No. 3,717,655 to Godefroi et al. This methodcomprises reacting a halomethyl naphthyl ketone with imidazole in aninert organic solvent. The starting halomethyl naphthyl ketones areknown or may be prepared by halogenation of the corresponding methylnaphthyl ketone by known means, for example, utilizing cupric bromide.The preparation of ketones of formula (I)d by the above described methodmay be carried out in an inert organic solvent, for example,dimethylformamide at a temperature between about -10° and +80° C.

Since not all possible combinations of substituted acetylnaphthalenesare known in the literature, the present invention is necessarilylimited to those substitution patterns which are preparable byapplication of known methods.

Preparation of compounds of formula (I)a wherein Z is hydroxymethylenemay be accomplished by the reduction of the corresponding ketone or acidaddition salt thereof under standard conditions, for example, by the useof sodium tetrahydroborate in a protic solvent, for example, methanol,at a temperature between about -20° and +20° C.

Compounds of formula (I)b wherein Z is esterified hydroxymethylene maybe prepared under usual esterification conditions from the correspondingalcohol by treatment of the alcohol with the desired acid halide oranhydride preferably in the presence of a base, preferably a tertiaryamine such as pyridine or triethylamine, at a temperature between about0° and +40° C. in a solvent such as pyridine, tetrahydrofuran,dichloromethane, chloroform, and the like.

Compounds of formula (I)c wherein Z is C₁ to C₆ alkoxymethylene and Rand m are as defined above, may be prepared from the correspondingalcohol by alkylation with Alk-X where X is a leaving group e.g. ahalide, especially bromide or iodide, or a reactive ester such as asulfonate ester, e.g. methanesulfonate or p-toluenesulfonate and Alk isas previously defined. In this method the alcohol is first converted toa metal salt, preferably an alkali metal salt, e.g. the sodium salt, andcontacted with Alk-X in an inert organic solvent such ashexamethylphosphoramide, dimethylformamide or tetrahydrofuran at atemperature between about -20° and 80° C., preferably between 0° and 55°C.

Compounds of formula (I)c wherein Z is alkylthiomethylene may beprepared in a two step procedure starting from the correspondingalcohol. In this procedure the alcohol is first converted to a leavinggroup such as a halide (e.g. chloride or bromide) or a reactive estersuch as a sulfonate ester (e.g., a methanesulfonate andp-toluenesulfonate ester) by conventional means well known in the artbefore conversion to the thioether. Preparation of the thioether isaccomplished by reaction of the intermediate halide or reactive esterwith an alkylthiol optionally in the presence of base or preferably witha salt of the thiol, preferably an alkali metal salt e.g. the sodiumsalt in an inert solvent such as tetrahydrofuran, methanol at atemperature of 0° to 67° C.

Certain compounds of formula (I)e wherein Z is ketal-protected carbonylmay be prepared by treatment of the corresponding ketone (or an acidaddition salt thereof) with the desired dihydric alcohol in the presenceof a strong acid, for example a sulfonic acid such as p-toluenesulfonicacid or a Lewis acid such as boron trifluoride. Water is preferablyremoved as an azeotrope with the solvent, for example an aromatichydrocarbon such as benzene or toluene, at a temperature sufficient toeffect such azeotropic removal, e.g. from about 75° to about 150° C.

Compounds of formula (I)e wherein Z is thioketal-protected carbonyl maybe prepared by treatment of the corresponding ketone (or an acidaddition salt thereof) with the desired thiol or dithiol, optionally inthe presence of a mineral acid such as hydrochloric acid, an organicsulfonic acid such as methanesulfonic acid or a Lewis acid such as borontrifluoride or zinc chloride at a temperature between about 0° and 100°C., preferably between about 0° and 25° C.

Compounds of formula (I)e wherein Z is hemithioketal-protected carbonylmay be prepared by treatment of the corresponding ketone with thedesired mercaptoalkanol under conditions similar to those describedabove for ketal formation.

Compounds of formula (I)e wherein Z is ketal-protected carbonyl may alsobe prepared according to the following reaction sequence: ##STR9##wherein X is halo (especially chloro or bromo) and m and R are aspreviously defined, as disclosed in U.S. Pat. Nos. 3,793,453 and3,575,999, in the corresponding phenyl series. In this sequence thenaphthyl methyl ketone is either first halogenated to the naphthylhalomethyl ketone, followed by ketalization or both steps are performedconcurrently. Ketalization to form cyclic ketals may be performedessentially as described above. Ketalization to form acyclic ketals maybe performed by employing an orthoester (e.g. methyl orthoformate orethyl orthoformate) in the presence of an organic, inorganic or Lewisacid, e.g. boron trifluoride, p-toluenesulfonic acid, perchloric acid,fuming sulfuric acid, and the like. The haloketal (II) is then convertedto (I)e by treatment with an alkali metal salt, e.g. the sodium salt, ofimidazole in a polar aprotic solvent such as dimethylformamide,dimethylsulfoxide or tetrahydrofuran at a temperature between about 20°and 130° C.

Compounds of formula (I)a wherein Z is hydroxymethylene may also beprepared according to the following reaction sequence: ##STR10## whereinthe epoxide (III) or the halohydrin (IV) is treated with imidazoleand/or an alkali metal salt (preferably the sodium salt) thereof in apolar aprotic solvent such as dimethylformamide, dimethylsulfoxide ortetrahydrofuran at a temperature between about 0° and 100° C. Treatmentof the epoxide requires one mole of imidazole in the presence of 0.05 to1 mole of imidazole salt.

Treatment of the halohydrin requires slightly over one mole of imidazolesalt, since the halohydrin is first converted in situ to the epoxide.

The subject compounds of formula (I) can be isolated as free bases;however, since many of the compounds in base form are oils and gumsand/or not water soluble it is often more convenient to isolate andfurther characterize such compounds as acid addition salts. These saltsare prepared in the usual manner, i.e., by reaction of the free basewith a suitable inorganic or organic acid. If desired, the salt can bereadily converted to the free base by treatment with a base such aspotassium or sodium carbonate or potassium or sodium hydroxide.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meanings indicated. The term"C₁ to C₆ alkyl" is intended to mean a straight or branched chainmonovalent substituent consisting of solely carbon and hydrogencontaining no unsaturation and having from 1 to 6 carbon atoms. Examplesof such alkyl groups include methyl, ethyl, i-propyl, n-hexyl and thelike. The term "C₁ to C₆ alkoxy" refers to the above alkyl groups linkedthrough an ether linkage and having the free valence from the oxygen.Examples of such alkoxy groups include methoxy, ethoxy, i-propoxy,hexyloxy and the like. The term "halo" refers to the groups fluoro,chloro, bromo or their corresponding halides.

The term "esterified hydroxymethylene" refers to a hydroxymethylenegroup which has been esterified with an alkanoic acid having from 1 to 6carbon atoms preferably 1 to 4 carbon atoms or with benzoic acidoptionally substituted with one to three substituents independentlyselected from C₁ to C₆ alkyl, C₁ to C₆ alkoxy and halo, preferablybenzoic acid. Typical alkanoic acids include formic acid, acetic acid,propionic acid, butyric acid, isobutyric acid, valeric acid, isovalericacid, caproic acid, and the like. The term "alkoxymethylene" refers to ahydroxymethylene group alkylated on the oxygen with a C₁ to C₆preferably C₁ to C₄ alkyl group. The term "alkylthiomethylene" refers toa mercapto-methylene group alkylated on sulfur with a C₁ to C₆preferably a C₁ to C₄ alkyl group. The term "ketal-protected carbonyl"refers to (i) a carbonyl group protected as an acyclic ketal derivedfrom a monohydric straight chain alkanol having from 1 to 4 carbon atomssuch as, for example, the dimethyl-, diethyl-, di(n-propyl)- anddi(n-butyl) ketals and (ii) a carbonyl group protected as a cyclic ketalderived from a dihydric alcohol having 2 or 3 carbon atoms which mayoptionally be substituted by one or more methyl groups, for example theethylenedioxy-, 1,3-propylenedioxy-, 1,2-propylenedioxy-,2,2-dimethyl-1,3-propylenedioxy, 1-methyl-1,3-propylenedioxy,1,3-dimethyl-1,3-propylenedioxy- and 2,3-butylenedioxyketals. The term"thioketal-protected carbonyl" is intended to mean (i) a carbonyl groupprotected as an acyclic thioketal derived from a straight or branchedchain alkylthiol having from 1 to 4 carbon atoms, such as thebis(methylthio)-, bis(ethylthio)-, bis(n-propylthio)-,bis(isopropylthio)- and bis(isobutylthio)-ketals, or from thiophenol orbenzyl mercaptan (i.e. the bis(phenylthio)- and bis(benzylthio)-ketals), and (ii) a carbonyl group protected as a cyclic thioketalderived from an alkylenedithiol having 2 or 3 carbon atoms which mayoptionally be substituted by one or more methyl groups, for example, theethylenedithio-, 1,3-propylenedithio- and 2,2-dimethyl-1,3-propylene-dithioketals. The term "hemithioketal-protected carbonyl" shall mean acarbonyl group protected as a cyclic hemithioketal derived from2-mercaptoethanol or 3-mercapto-1-propanol. The term "pharmaceuticallyacceptable acid addition salts" refers to salts of the free bases offormula (I), which salts possess the desired pharmacological activityand which are neither biologically nor otherwise undesirable. Such saltsmay be formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or withorganic acids such as acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, and the like.

Compounds of formula (I) wherein Z is hydroxymethylene, esterifiedhydroxymethylene, alkoxymethylene, alkylthiomethylene or hemithioketalprotected carbonyl possess a chiral center. Accordingly, these compoundsmay be prepared in either optically active form, or as a racemicmixture. Unless otherwise specified, the compounds described herein areall in the racemic form. However, the scope of the subject invention isnot to be limited to the racemic form but is to encompass the individualoptical isomers of the subject compounds.

If desired, compounds of formula (I) wherein Z is hydroxymethylene,esterified hydroxymethylene, alkoxymethylene, alkylthiomethylene orhemithioketal protected carbonyl may be prepared in optically activeform by conventional resolution means known per se, for example, by theseparation (e.g., fractional crystallization) of the diastereomericsalts formed by reaction of, e.g., racemic compounds of formula (I)wherein Z is hydroxymethylene, esterified hydroxymethylene,alkoxymethylene, alkylthiomethylene or hemithioketal protected carbonylwith an optically active acid or by separation of the diastereomericesters formed by reaction of such a racemic alcohol wherein Z ishydroxymethylene with an optically active acid. Exemplary of suchoptically active acids are the optically active forms ofcamphor-10-sulfonic acid, α-bromocamphor-π-sulfonic acid, camphoricacid, menthoxyacetic acid, tartaric acid, malic acid, diacetyltartaricacid, pyrrolidone-5-carboxylic acid, and the like. The separated purediasteromeric salts or esters may then be cleaved by standard means toafford the respective optical isomers of the desired compound.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the present invention.It should not be considered as a limitation upon the scope of theinvention but merely as illustrative and representative thereof.

Preparation 1

Methyl 2-(6,7-dimethylnaphthyl) ketone (1.32 g.), in 40 ml of a 1:1mixtureof chloroform and ethyl acetate is treated with 2.97 g. of copper(II) bromide. The resulting reaction mixture is heated under reflux withvigorous stirring overnight, the solvent is removed, ether added and thecopper (I) bromide removed by filtration. Evaporation of the filtrateunder reduced pressure yields crude bromomethyl 2-(6,7-dimethylnaphthyl)ketone, used directly in the next step.

Preparation 2

Chloroacetyl chloride (15.9 ml) is added to a mixture of 26.67 g ofanhydrous aluminum chloride in 35 ml of nitrobenzene at 0° followedbythe dropwise addition with stirring of 31.25 g of 2-ethylnaphthaleneover 15 minutes. After stirring overnight at room temperature themixture is poured on to a mixture of 500 g of ice and 100 mlconcentrated hydrochloric acid. This is then extracted with ethylacetate, the extractswashed with aqueous potassium carbonate, dried(MgSO₄) and evaporated.After distillation of the nitrobenzene, themixture is distilled as a yellow oil at 177° (0.4 mm). The resultingmixture of isomers is chromatographed on silica gel eluting with tolueneto give 8.75 g of pure 1-chloroacetyl-7-ethylnaphthalene as an oil; and6.3 g of 2-chloroacetyl-6-ethylnaphthalene as a colorless solid,recrystallized from hexane with mp 75°-76.5° C.

Preparation 3

A mixture of 20 g. of anhydrous aluminum chloride and 30 ml nitrobenzeneistreated at room temperature with 8.3 ml of chloroacetyl chloride andwarmedto dissolve solids. At room temperature, 25.54 g of a mixture ofisopropylnaphthalene isomers is added dropwise and the mixture stirredforfour hours and worked up as in Preparation 1. The resulting crudedark oil is distilled at 185° (0.19 mm) to give 22 g of an amber oilcontaining at least four products. The mixture is chromatographed onsilica gel eluting with 25% toluene/hexane to give pure1-chloroacetyl-4-isopropylnaphthalene as an oil.

Example 1

To a stirred, ice-cooled solution of 7.07 g. of imidazole in 15 ml. ofdimethylformamide is added 5.5 g. of chloromethyl 1-(7-methylnaphthyl)ketone in 10 ml dimethylformamide. The mixture is stirred at roomtemperature overnight and for 2 hours at 80° C. The solution is pouredinto water, the product extracted with ether and the extracts washedwith water and dried (MgSO₄). The product is converted to itshydrobromide acid addition salt by addition of ethereal hydrogen bromideuntil precipitation is complete. The resulting solid is recrystallizedfrom acetone to yield colorless crystals of1-[(7-ethyl-1-naphthoyl)methyl]imidazole hydrobromide, m.p.187.5°-190.5° C.

Repeating the procedure of Example 1, utilizing the appropriatelysubstituted-naphthyl bromo(chloro)methyl ketone there may be prepared:

1-[(6-bromo-2-naphthoyl)methyl]imidazole hydrochloride, m.p. 283.5°-287°C.;

1-[(6-chloro-2-naphthoyl)methyl]imidazole hydrochloride, m.p. 277°-279°C.;

1-[(6-fluoro-2-naphthoyl)methyl]imidazole;

1-[(6-methyl-2-naphthoyl)methyl]imidazole hydrochloride, m.p. 271°-272°C. (d);

1-[(1-methyl-2-naphthoyl)methyl]imidazole;

1-[(3-methyl-2-naphthoyl)methyl]imidazole;

1-[(5-methyl-2-naphthoyl)methyl]imidazole;

1-[(6-ethyl-2-naphthoyl)methyl]imidazole hydrobromide, m.p. 263.5°-264°C.;

1-[(6-i-propyl-2-naphthoyl)methyl]imidazole;

1-[(6-t-butyl-2-naphthoyl)methyl]imidazole;

1-[(6,7-dimethyl-2-naphthoyl)methyl]imidazole hydrochloride, m.p.239.5°-242° C. (d);

1-[(1,4-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(1,6-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(3,7-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(5,8-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(3,6-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(6,8-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(4,5-dimethyl-2-naphthoyl)methyl]imidazole;

1-[(1-methoxy-2-naphthoyl)methyl]imidazole hydrochloride, m.p.170°-172.5° C.;

1-[(6-methoxy-2-naphthoyl)methyl]imidazole hydrochloride, m.p.233°-237.5° C. (d);

1-[(6-ethoxy-2-naphthoyl)methyl]imidazole;

1-[(6-hydroxy-2-naphthoyl)methyl]imidazole hydrochloride, m.p. 264°-268°C.;

1-[(1-hydroxy-2-naphthoyl)methyl]imidazole;

1-[(7-bromo-1-naphthoyl)methyl]imidazole;

1-[(3-bromo-1-naphthoyl)methyl]imidazole;

1-[(7-methyl-1-naphthoyl)methyl]imidazole hydrochloride, m.p.241.5°-244° C.;

1-[(4-methyl-1-naphthoyl)methyl]imidazole;

1-[(7-ethyl-1-naphthoyl)methyl]imidazole hydrochloride;

1-[(7-ethyl-1-naphthoyl)methyl]imidazole hydrobromide, m.p.187.5°-190.5° C.;

1-[(4-ethyl-1-naphthoyl)methyl]imidazole;

1-[(4-i-propyl-1-naphthoyl)methyl]imidazole hydrochloride, m.p.199.5°-203° C.;

1-[(6,7-dimethyl-1-naphthoyl)methyl]imidazole hydrochloride, m.p.271°-274° C. (d);

1-[(6,7-dimethoxy-1-naphthoyl)methyl]imidazole hydrochloride, m.p.267.5°-270° C.;

1-[(2,3-dimethyl-1-naphthoyl)methyl]imidazole;

1-[(2,6-dimethyl-1-naphthoyl)methyl]imidazole;

1-[(3,6-dimethyl-1-naphthoyl)methyl]imidazole; and

1-[(3,4-diethyl-1-naphthoyl)methyl]imidazole.

EXAMPLE 2

To 2.1 g. of the above obtained 1-[(7-ethyl-1-naphthoyl)methyl]imidazolehydrobromide in 50 ml. of methanol at 0°-5° C. is added, with stirring,excess sodium tetrahydroborate. After stirring for 30 minutes at 0° C.,the reaction mixture is evaporated to dryness. The resultant residue istreated with water and the product which crystallizes is filtered off,washed with water and recrystallized from ethyl acetate to yield1-[2-hydroxy-2-(7-ethyl-1-naphthyl)ethyl]imidazole.

Similarly there may be prepared the following:

1-[2-hydroxy-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-n-propyl-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-i-propyl-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-t-butyl-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-chloro-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(6-bromo-2-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(4-methyl-1-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(4-ethyl-1-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(4-i-propyl-1-naphthyl)ethyl]imidazole;

1-[2-hydroxy-2-(7-methyl-1-naphthyl)ethyl]imidazole; and

1-[2-hydroxy-2-(7-ethyl-1-naphthyl)ethyl]imidazole.

EXAMPLE 3

A mixture of 0.7 g. of 1-[(6-ethyl-2-naphthoyl)methyl]imidazole, 4 ml ofethylene glycol and 1.3 g. of anhydrous p-toluenesulfonic acid in 50 ml.of toluene is heated overnight under reflux through a Dean-Stark trap.Thetrap is the replaced by a separatory funnel containing 4 A molecularsievesand heating is continued for a further day. After cooling, themixture is treated with 100 ml. of ethyl acetate, neutralized by pouringinto excess aqueous potassium carbonate and the organic phase separated,washed with water, dried (MgSO₄) and evaporated to afford1-[2,2-ethylenedioxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole. This ispurified by chromatography on silica gel eluting with 10%methanol/dichloromethane and the hydrochloride salt prepared by dropwiseaddition of ethereal hydrogen chloride until precipitation is complete.Filtration and recrystallization from acetone/methanol gives 0.38 g.pure hydrochloride, m.p. 251° C.

Repeating the procedure above utilizing the appropriate startingmaterials there may be prepared:

1-[2,2-(1,3-propylenedioxy)-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-(2,2-dimethyl-1,3-propylenedioxy)-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-(1-methyl-1,3-propylenedioxy)-2-(6-chloro-2-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedioxy-2-(7-ethyl-1-naphthyl)ethyl]imidazole;

1-[2,2-(1,3-propylenedioxy)-2-(7-ethyl-1-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedioxy-2-(4-isopropyl-1-naphthyl)ethyl]imidazole;

1-[2,2-(1,2-propylenedioxy)-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedioxy-2-(7-methyl-1-naphthyl)ethyl]imidazole;

1-[2,2-(2,3-butylenedioxy-2-(6,7-dimethyl-2-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedioxy-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedioxy-2-(4-methyl-1-naphthyl)ethyl]imidazole; and

1-[2,2-ethylenedioxy-2-(4-ethyl-1-naphthyl)ethyl]imidazole.

EXAMPLE 4

A solution of 1.00 g. of 1-[(6-bromo-2-naphthoyl)methyl]imidazolehydrochloride in 6 ml. of 98% methanesulfonic acid is treated at roomtemperature with 4 ml. of ethyl mercaptan and the mixture stirredovernight under nitrogen. The resulting solution is added to excessaqueous potassium carbonate, the product extracted with ethyl acetateand the extracts washed, dried (MgSO₄) and evaporated. The residue waschromatographed on silica gel eluting with 5% acetone in dichloromethaneand the resulting pure1-[2,2-bis(ethylthio)-2-(6-bromo-2-naphthyl)ethyl]imidazole dissolved inether. Dropwise addition of ethereal hydrogen chloride precipitates 0.62g. of the hydrochloride which is recrystallized from ethylacetate/methanol to give 0.46 g. pure product, m.p. 216°-217.5° C.

Repeating the procedure above utilizing the appropriate startingmaterials there may be prepared:

1-[2,2-bis(methylthio)-2-(6-ethyl-2-naphthyl)ethyl]imidazole;

1-[2,2-bis(ethylthio)-2-(6-ethyl-2-naphthyl)ethyl]imidazole-hydrochloridesalt, m.p. 130° C.;

1-[2,2-bis(n-propylthio)-2-(6-bromo-2-naphthyl)ethyl]imidazole-hydrochloridesalt, m.p. 183.5°-184.5° C.;

1-[2,2-bis(isobutylthio)-2-(6-methoxy-2-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedithio-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-(1,3-propylenedithio)-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2,2-bis(ethylthio)-2-(6,7-dimethyl-2-naphthyl)ethyl]imidazole-hydrochloridesalt, m.p. 195°-198° C.;

1-[2,2-bis(isopropylthio)-2-(4-methyl-1-naphthyl)ethyl]imidazole;

1-[2,2-ethylenedithio-2-(4-ethyl-1-naphthyl)ethyl]imidazole;

1-[2,2-bis(ethylthio)-2-(7-methyl-1-naphthyl)ethyl]imidazole;

1-[2,2-bis(n-propylthio)-2-(6,7-dimethyl-2-naphthyl)ethyl]imidazole-hydrochloridesalt, m.p. 140°-145,5° C.;

1-[2,2-bis(n-butylthio)-2-(2-methoxy-1-naphthyl)ethyl]imidazole;

1-[2,2-bis(phenylthio)-2-(6-hydroxy-2-naphthyl)ethyl]imidazole; and

1-[2,2-bis(benzylthio)-2-(6-methoxy-2-naphthyl)ethyl]imidazole.

EXAMPLE 5

A solution of 1.26 g.1-[2-hydroxy-2-(6-methyl-2-naphthyl)ethyl]imidazole in 20 ml. pyridineis treated dropwise with stirring with 0.72 ml. of benzoyl chloride andthe mixture stirred overnight. The resulting solutionis poured into 100ml. water, extracted with ethyl acetate and the extractswashed, dried(MgSO₄) and evaporated in vacuo to remove residual pyridine and afford1-[2-benzoyloxy-2-(6-methyl-2-naphthyl)ethyl]imidazole. The residue isdissolved in ether, treated with ethereal hydrogen chloride and theresulting precipitate recrystallized from acetone/methanol to give thehydrochloride salt.

EXAMPLE 6

To a solution of 2.38 g. of1-[2-(6-methyl-2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. ofhexamethylphosphoramide under nitrogen is added 480 mg. of a 56%dispersion of sodium hydride in mineral oil. After stirring for 1 hourat room temperature, the temperature is adjusted to 50° C. and stirringis continued for 1 to 2 hours. The reaction mixture is then cooled toabout 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter,the solution is stirred at 5° to 10° C. for 1 hour, at room temperaturefor 4 hours and then heated at 50° C. for 2 hours. The reaction mixtureis then poured into water and the resultant aqueous mixture extractedwith ether and the ether extracts washed with water. The organic phaseis dried over magnesium sulfate and evaporated. The resulting residuemay be chromatographed on silica gel to effect purification of the freebase. Elution of the gel with 5 to 10% methanol in dichloromethaneyields 1-[2-(6-methyl-2-naphthyl)-2-(methoxy)ethyl]imidazole.

The hydrochloride salt of the free base is prepared by the dropwiseaddition of ethereal hydrogen chloride to the free base in ether. Whenprecipitation is complete the salt is collected by filtration andrecrystallized from ethyl acetate/methanol to yield1-[2-(6-methyl-2-naphthyl)-2-(methoxy)ethyl]imidazole hydrochloride.

Repeating the above procedure using the appropriate starting materialsthere may be prepared:

1-[2-(6-ethyl-2-naphthyl)-2-(methoxy)ethyl]imidazole;

1-[2-(6-methyl-2-naphthyl)-2-(ethoxy)ethyl]imidazole;

1-[2-(4-methyl-1-naphthyl)-2-(methoxy)ethyl]imidazole;

1-[2-(4-ethyl-1-naphthyl)-2-(methoxy)ethyl]imidazole;

1-[2-(4-isopropyl-1-naphthyl)-2-(methoxy)ethyl]imidazole;

1-[2-(7-methyl-1-naphthyl)-2-(methoxy)ethyl]imidazole; and

1-[2-(7-ethyl-1-naphthyl)-2-(methoxy)ethyl]imidazole.

EXAMPLE 7

Thionyl chloride (5 ml.) and 2.0 g. of1-[2-(6-methyl-2-naphthyl)-2-hydroxyethyl]imidazole are stirred at roomtemperature for about 20 minutes. Thereafter, the solution is evaporatedto dryness and the residue is treated with ethyl acetate and filtered toyield 1-[2-(6-methyl-2-naphthyl)-2-chloroethyl]imidazole hydrochloride.

The above obtained chloride, i.e.,1-[2-(6-methyl-2-naphthyl)-2-chloroethyl]imidazole hydrochloride (1.0g.) is added to the salt prepared in situ from 0.78 g. of n-propylmercaptan and 380 mg. of sodium hydride (56% dispersion in mineral oil)in 50 ml. ofdry tetrahydrofuran. The mixture is stirred for 4 hours at25° C. and then evaporated to dryness. The residue is extracted withether and the ether extracts washed with water, dried over magnesiumsulfate and evaporated. The resulting residue may be chromatographed onsilica gel to effect purification of the free base. Elution of the gelwith 5 to 10% acetone in dichloromethane yields1-[2-(6-methyl-2-naphthyl)-2-(n-propylthio)ethyl]imidazole.

The nitrate salt of the free base is prepared by the dropwise additionof concentrated nitric acid (d=1.42) to the free base in ether. Whenprecipitation is complete the product is collected by filtration andrecrystallized from ethyl acetate to yield1-[2-(6-methyl-2-naphthyl)-2-(n-propylthio)ethyl]imidazole nitrate.

Repeating the above procedure using the appropriate starting materialsthere may be prepared:

1-[2-(6-methyl-2-naphthyl)-2-(methylthio)ethyl]imidazole;

1-[2-(6-ethyl-2-naphthyl)-2-(methylthio)ethyl]imidazole;

1-[2-(7-methyl-1-naphthyl)-2-methylthio)ethyl]imidazole;

1-[2-(7-ethyl-1-naphthyl)-2-methylthio)ethyl]imidazole;

1-[2-(4-methyl-1-naphthyl)-2-methylthio)ethyl]imidazole;

1-[2-(4-ethyl-1-naphthyl)-2-methylthio)ethyl]imidazole; and

1-[2-(4-isopropyl-1-naphthyl)-2-methylthio)ethyl]imidazole.

EXAMPLE 8

Repeating the procedure of Example 5, utilizing the appropriate startingmaterial, there may be prepared the following compounds:

1-[2-acetoxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole;

1-[2-propionyloxy-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2-butyryloxy-2-(6-methyl-2-naphthyl)ethyl]imidazole;

1-[2-isobutyryloxy-2-(6-chloro-2-naphthyl)ethyl]imidazole;

1-[2-hexanoyloxy-2-(6-methoxy-2-naphthyl)ethyl]imidazole;

1-[2-acetoxy-2-(4-ethyl-1-naphthyl)ethyl]imidazole;

1-[2-propionyloxy-2-(4-methyl-1-naphthyl)ethyl]imidazole;

1-[2-butyryloxy-2-(7-methyl-1-naphthyl)ethyl]imidazole;

1-[2-isobutyryloxy-2-(7-ethyl-1-naphthyl)ethyl]imidazole;

1-[2-hexanoyloxy-2-(2-methoxy-1-naphthyl)ethyl]imidazole; and

1-[2-benzoyloxy-2-(2-methoxy-1-naphthyl)ethyl]imidazole.

EXAMPLE 9

A solution of 2.63 g. of bromomethyl 2-(6-methylnaphthyl) ketone, 1.7 g.trimethyl orthoformate and a few crystals of p-toluenesulfonic acid(anhydrous) in 20 ml. anhydrous methanol is heated under reflux for twohours. After cooling to room temperature, two drops of phenolphthaleinsolution are added and a solution of sodium methoxide in methanol isaddeddropwise until a pink color persists. After removal of the solventunder reduced pressure the resulting oil is dissolved in ether,decolorized withcharcoal and the ether removed to give 3.11 g. (100%) ofbromomethyl 2-(6-methylnaphthyl)ketone dimethyl ketal as a colorlessoil.

Sodium hydride (0.40 g. of 50% dispersion in mineral oil) is added to0.61 g. imidazole in 10 ml dimethylformamide and the mixture stirred atroom temperature until the evolution of hydrogen is complete.Bromomethyl 2-(6-methylnaphthyl)ketone dimethyl ketal (2.31 g.) in 5 mldimethylformamide is then added and the mixture stirred for 24 hours at110° under nitrogen. The resulting solution is poured into water (400ml.), extracted with ether (400 ml. total), and the extracts washed,dried (MgSO₄) and evaporated. The resulting crude solid (2.3 g.) isrecrystallized from toluene to give1-[2-(6-methyl-2-naphthyl)-2,2-dimethoxyethyl]imidazole as a colorlesssolid.

EXAMPLE 10

1-[(6-Ethyl-2-naphthoyl)methyl]imidazole hydrochloride (600 mg.) andp-toluenesulfonic acid monohydrate (570 mg.) in toluene (10 ml.)containing a little benzene are treated with 2-mercaptoethanol (4 ml.).Apressure-equalized addition funnel filled with activated 4 A molecularsieves in toluene is placed above the flask as a modified Dean-Starktrap and the mixture heated under reflux with stirring for 18 hours. Theresulting mixture is then added with stirring to excess aqueouspotassium carbonate, the product extracted with ether (with filtration)and the extracts washed, dried (MgSO₄) and evaporated. Purification bychromatography on silica gel eluting with ethyl acetate gives pure1-[(6-ethyl-2-naphthoyl)methyl]imidazole ethylene hemithioketal.

EXAMPLE 11

Ethereal hydrogen chloride is added dropwise to a solution of 1.0 g.1-[(6-methyl-2-naphthoyl)methyl]imidazole in 100 ml. ether untilprecipitation is complete. The product is filtered, washed with ether,airdried and recrystallized from methanol/acetone to yield1-[(6-methyl-2-naphthoyl)methyl]imidazole hydrochloride, m.p. 271°-272°C. (decomp).

In a similar manner, all compounds of formula (I) in free base form maybe converted to the acid addition salts by treatment with theappropriate acid, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinicacid, malic acid, maleicacid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, and the like.

EXAMPLE 12

1-[(6-Methyl-2-naphthoyl)methyl]imidazole hydrochloride (1.0 g.)suspended in 50 ml. of ether is stirred with excess dilute aqueouspotassium carbonate solution until the salt is completely dissolved. Theorganic layer is then separated, washed twice with water, dried overmagnesium sulfate and evaporated to yield1-[(6-methyl-2-naphthoyl)methyl]imidazole.

In a similar manner the acid addition salts of all compounds of formula(I)may be converted to the corresponding compounds in free base form.

EXAMPLE 13

The following illustrates a pharmaceutical composition for oraladministration which may be prepared for the compounds of the presentinvention, e.g.

1-[(7-ethyl-1-naphthoyl)methyl]imidazole hydrobromide,

    ______________________________________                                                       parts by weight                                                ______________________________________                                        Active compound  200                                                          Magnesium stearate                                                                             3                                                            Starch           30                                                           Lactose          116                                                          Polyvinylpyrrolidone                                                                           3                                                            ______________________________________                                    

The above ingredients are combined and granulated using methanol as thesolvent. The formulation is then dried and formed into tablets(containing200 mg. of active compound each) with an appropriatetabletting machine.

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications can be made to adapt aparticular situation, material or composition of matter, process,process step or steps or objective to the spirit of this inventionwithout departing from its essential teachings.

What is claimed is:
 1. A compound of the formula ##STR11## wherein m isan integer of 1, 2 or 3; R is independently selected from the group C₁to C₆ alkyl, C₁ to C₆ alkoxy, halo, trifluoromethyl and hydroxy; Ke isselected from the group (i) a carbonyl group protected as an acyclicketal derived from a monohydric straight chain alkanol having from oneto four carbon atoms, (ii) a carbonyl group protected as a cyclic ketalwherein the cyclic ketal is selected from the group consisting ofethylenedioxy, 1,3-propylenedioxy, 1,2-propylenedioxy,2,2-dimethyl-1,3-propylenedioxy, 1-methyl-1,3-propylenedioxy,1,3-dimethyl-1,3-propylenedioxy and 2,3-butylenedioxy, (iii) a carbonylgroup protected as an acyclic thioketal derived from a straight orbranched chain alkylthio having from one to four carbon atoms or fromthiophenol or benzylmercaptan, (iv) a carbonyl group protected as acyclic thioketal derived from an alkylene dithio having two or threecarbon atoms which may optionally be substituted by one or more methylgroups, or (v) a carbonyl group protected as a cyclic hemithioketalderived from 2-mercaptoethanol or 3-mercapto-1-propanol; and thepharmaceutically acceptable acid addition salts thereof.
 2. The compoundof claim 1 wherein Ke is (i) a carbonyl group protected as an acyclicketal derived from a monohydric straight chain alkanol having from oneto four carbon atoms, (ii) a carbonyl group protected as a cyclic ketalwherein the cyclic ketal is selected from the group consisting ofethylenedioxy, 1,3-propylenedioxy, 1,2-propylenedioxy,2,2-dimethyl-1,3-propylenedioxy, 1-methyl-1,3-propylenedioxy,1,3-dimethyl-1,3-propylenedioxy and 2,3-butylenedioxy, (iii) a carbonylgroup protected as an acyclic thioketal derived from a straight orbranched chain alkylthio having from one to four carbon atoms or fromthiophenol or benzylmercaptan, or (iv) a carbonyl group protected as acyclic thioketal derived from an alkylene dithio having two or threecarbon atoms which may optionally be substituted by one or more methylgroups, R is selected from the group C₁ to C₄ alkyl and halo; and m isthe integer 1 or 2 and the pharmaceutically acceptable acid additionsalts thereof.
 3. The compound of claim 2 wherein Ke is (i) a carbonylgroup protected as an acyclic ketal derived from a monocyclic straightchain alkanol having one to four carbon atoms or (ii) a carbonyl groupprotected as a cyclic ketal wherein the cyclic ketal is selected fromthe group consisting of ethylenedioxy, 1,3-propylenedioxy,1,2-propylenedioxy, 2,2-dimethyl-1,3-propylenedioxy,1-methyl-1,3-propylenedioxy, 1,3-dimethyl-1,3-propylenedioxy and2,3-butylenedioxy, R is methyl, ethyl, chloro or bromo; and m is theinteger 1 and the pharmaceutically acceptable acid addition saltsthereof.
 4. The compound of claim 3 that is1-[2,2-ethylenedioxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole and thepharmaceutically acceptable acid addition salts thereof.
 5. Apharmaceutical composition useful for treating or preventing convulsionsin a mammalian subject which comprises a therapeutically effectiveamount of a compound of claim 1 in admixture with a pharmaceuticallyacceptable, non-toxic carrier.
 6. A pharmaceutical composition usefulfor inhibiting gastric secretion in a mammalian subject which comprisesa therapeutically effective amount of a compound of claim 1 in admixturewith a pharmaceutically acceptable, non-toxic carrier.
 7. A method oftreating or preventing convulsions in a mammalian subject whichcomprises administering a therapeutically effective amount of a compoundof claim 1 to a mammalian subject in need of such treatment.
 8. A methodof inhibiting gastric secretion in a mammalian subject which comprisesadministering a therapeutically effective amount of a compound of claim1 to a mammalian subject in need of such treatment.